Drug-induced hepatotoxicity is an adverse effect of medications that manifests in susceptible individuals and in different ways.

A multidisciplinary research team, led by scientists from the University of Valencia and the La Fe Health Research Institute (ISS La Fe) in Valencia, has made significant advances in understanding drug-induced liver injury (DILI). Through metabolomic analysis, the study has revealed a wide variability in patients' responses to this type of toxicity, opening new avenues for more precise diagnostics and improved clinical monitoring.

The innovative study from the Mixed Unit (University of Valencia-IIS La Fe) of Experimental Hepatology, titled "Exploring individual variability in drug-induced liver injury (DILI) responses through Metabolomic Analysis" (DOI: 10.3390/ijms25053003), has shown that by analyzing hepatic metabolite profiles detected in patients' plasma, it is possible to understand the nature and management of drug-induced hepatotoxicity (DILI).

DILI is a severe and heterogeneous hepatic complication with significant diagnostic and prognostic challenges. Firstly, it is difficult to diagnose because it presents signs and symptoms that are common to most liver conditions. Therefore, its diagnosis is made by excluding other liver pathologies and using probability scales. Traditionally, drug-induced liver damage presents in several phenotypes: hepatocellular, cholestatic, or mixed, which are classified based on the levels of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) compared to normal levels. This simplified approach does not fully capture the diversity of individual responses to the same drug or the dynamic progression of liver disease.

To examine in detail the different individual responses to drug-induced liver damage, a clinical study was designed in which plasma samples from 79 patients diagnosed unequivocally with DILI were examined. Metabolomic profiles were analyzed throughout the course of the disease to identify biomarkers representative of different types of cell damage (hepatocellular or cholestatic) and the differences between patients affected by the same drug. By integrating the data and constructing advanced predictive models, it was possible to quantify the contribution of each DILI subtype to a given patient's clinical picture, the severity of the damage (by how much the metabolic status of the same individual differed once their healthy state was restored), and how the magnitude and characteristics of liver damage evolved with the DILI process and its gradual recovery.

As Marta Moreno, researcher at the University of Valencia and lead author of the study, points out, “based on the models we had previously developed and validated (https://doi.org/10.1007/s00204-023-03474-8), we were able to apply our strategy to a) monitor individual variations in responses to the same medication, b) identify transitions between sub-phenotypes throughout the disease progression, and c) detect other metabolic features present in DILI that are not identified with standard clinical methods.”

In this type of study, “the precision of metabolomic analysis and the subsequent data processing is absolutely key to extracting clinically relevant information for the patient while also building predictive mathematical models,” said researcher Guillermo Quintas, who led this part of the study.

"Metabolomics applied to the study of hepatotoxicity is emerging as a powerful tool for examining changes in the metabolic pattern of cells, as a consequence of the damage they suffer due to hepatotoxicity. This intracellular pattern is reflected in the extracellular environment (exo-metabolome), and its analysis can infer the alterations that the cells or the organ are experiencing. From these changes in the metabolite pattern, we can deduce which metabolic alterations the cells are suffering. From here, a lot of useful information can be extracted to personalize diagnosis, monitoring, and treatment for DILI patients," said Professor José Castell from the University of Valencia, the study coordinator.

A renowned research team
The Mixed Unit of Experimental Hepatology, to which the authors of the study belong, is composed of teaching and research staff from the University of Valencia and the La Fe Health Research Institute. It is a research hub focused on the study of the liver, hepatic metabolism, and drug-induced hepatotoxicity, which has gained notable recognition for its extensive history and scientific contributions. The team is pioneering in establishing human hepatocyte cultures, developing predictive methods to identify the potential hepatotoxicity of new drugs, and cell therapy with hepatocytes. They have also been pioneers in applying metabolomics to the study of hepatotoxicity in patients and to study the mechanisms of hepatotoxicity.

The Unit is also part of CIBERHED (Liver and Digestive Diseases of the Carlos III Health Institute) and has had prominent and extensive participation in European Research Projects. Among the most recent are EUTOXRISK (An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century) and ONTOX (Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment), the latter of which is still ongoing.

This work was funded by the RYC2021-031346-I grant from MICIU/AEI/10.13039/501100011033, “European Union NextGenerationEU/PRTR,” and the Ministry of Education, Universities, and Employment of the Generalitat Valenciana (CIGE/2022/145).

For more information:

DOI: 10.3390/ijms25053003

For further details about this breakthrough and its potential clinical applications, please contact: marta.moreno.torres@uv.es